Structure-Based Design, Synthesis, and Evaluation of Novel Ponatinib Derivatives With a Significantly Altered
Tobias Betzholz1,2, Ting Liu1,2, Andreas Krämer3,4,5
1Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
Abstract:
The protein kinase inhibitor ponatinib is an approved anti-cancer drug that remains effective even against kinases with gatekeeper residue mutations. However, serious toxic side effects, particularly cardiotoxicity, prevent its widespread therapeutic use. The undesirable side effects have been attributed to non-selective inhibition of more than 60 kinases from both the tyrosine and serine/threonine kinase families. With the aim of greatly reducing the spectrum of inhibited kinases, we performed structure-based design and synthesis of novel ponatinib derivatives. By modifying the methylation pattern of the central benzamide ring and replacing the N-methylpiperazine end group with a propenylamine or propylamine chain, we discovered compound 5 displaying a significantly altered target kinase profile, with B-Raf and Flt-1 being its main targets. This specific target combination has not yet been described for a kinase inhibitor. Furthermore, two of the original off-target kinases that should not be inhibited to avoid cardiotoxicity, SLK and FGFR1, were no longer affected by 5. Interestingly, 5 almost completely retained the efficacy of ponatinib in inhibiting colony formation by MDA-MB-231 breast cancer cells. These results might support the development of novel ponatinib analogs toward therapeutic kinase inhibitors with improved pharmacological properties.
Insights
Researchers developed a novel ponatinib derivative, compound 5, which retains anti-cancer efficacy while reducing toxic side effects by altering its kinase inhibition profile. This new compound shows promise for safer cancer therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Ponatinib is an effective anti-cancer drug, but its use is limited by severe cardiotoxicity due to non-selective kinase inhibition.
- Over 60 kinases are inhibited by ponatinib, contributing to its broad efficacy and significant side effects.
Purpose of the Study:
- To design and synthesize novel ponatinib derivatives with a reduced kinase inhibition spectrum to improve safety.
- To identify compounds that maintain anti-cancer activity while minimizing off-target effects, particularly cardiotoxicity.
Main Methods:
- Structure-based design and synthesis of ponatinib derivatives.
- Modification of the benzamide ring methylation and N-methylpiperazine end group.
- Evaluation of target kinase profiles and in vitro anti-cancer efficacy.
Main Results:
- Compound 5 demonstrated a significantly altered kinase profile, primarily targeting B-Raf and Flt-1.
- Compound 5 no longer inhibited SLK and FGFR1, kinases associated with cardiotoxicity.
- Compound 5 retained significant efficacy in inhibiting MDA-MB-231 breast cancer cell colony formation.
Conclusions:
- Novel ponatinib analogs can be developed with improved pharmacological properties and reduced toxicity.
- Compound 5 represents a promising lead for developing safer and more effective kinase inhibitors.
- Targeted kinase inhibition strategies can mitigate drug-induced side effects in cancer therapy.
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